Altered vulnerability to the damaging effects of toxic chemicals may contribute significantly to the increased incidence of drug toxicity in elderly patients. The proposed studies are designed to provide information about the effects of aging on the susceptibility of the liver to toxicants that produce oxidative injury. A key feature of the project is that in vitro measurements of antioxidant defense systems will be correlated with toxicity studies in isolated hepatocytes and in intact animals. the rationals is to compare toxic responses and antioxidant defense systems among young-adult, middle-aged and old male Fischer 344 rats, a well-defined animal model of aging. Important findings will be confirmed using other rat and mouse strains. To determine the influence of aging on defense mechanisms that protect against oxidative stress enzymatic and nonenzymatic antioxidant systems will be measured in liver fractions prepared from the three age groups of rats. Antioxidants (vitamin E, glutathione, ascorbic acid and uric acid), peroxide- metabolizing enzymes (superoxide dismutase, glutathione peroxidase and catalase) and certain ancillary enzymes (glutathione reductase, glucose- 6-phosphate dehydrogenase, gemma-glutamylcysteine synthetase, glutathione synthetase) will be studied. Next, studies will determine if there are age-dependent differences in the response of isolated hepatocytes to diquat, an oxidative toxicant. Toxicity measurements in the hepatocytes will include cell viability, thiol status and lipid peroxidation. In vivo experiments will ascertain whether the age of the rats affects the extent of liver damage produced by the administration of a standard dose of diquat. Finally, studies will compare the ability of rats from the three age groups to induce the peroxide-metabolizing enzymes in response to a mild oxidative challenge (hydrogen peroxide in the drinking water for 30 days or a low dose of diquat for 10 days). The proposed research will provide firm a information about the effects of aging on vulnerability to oxidative stress. The long-term goal of this research is to understand how the elderly differ from younger individuals in their response to toxic drugs and chemicals.